Enhanced antitumor effect of novel dual-targeted paclitaxel liposomes

A novel dual-targeted peptide containing an alpha V integrins specific ligand and a neuropilin-1 specific motif was developed which showed an increased specific targeting affinity to tumors. Active dual-targeted liposomes were then produced with this peptide and exhibited greater binding activity than single-targeted liposomes in vitro. Paclitaxel entrapped in this formulation greatly increased the uptake of paclitaxel in the targeting cells and significantly suppressed the growth of HUVEC and A549 cells compared with general paclitaxel injections (Taxol) and single-targeted paclitaxel liposomes. The treatment of tumor xenograft models with dual-targeted paclitaxel liposomes also resulted in better tumor growth inhibition than any other treatment groups. Therefore, the dual-targeted paclitaxel liposomes prepared in the present study might be a more promising drug for cancer treatment. Furthermore, the dual-targeting approach may produce synergistic effects that can be applied in the development of new targeted drug delivery systems.

[1]  N. Oku,et al.  A novel DDS strategy, "dual-targeting", and its application for antineovascular therapy. , 2010, Cancer letters.

[2]  Klaas Nicolay,et al.  Synergistic targeting of alphavbeta3 integrin and galectin-1 with heteromultivalent paramagnetic liposomes for combined MR imaging and treatment of angiogenesis. , 2010, Nano letters.

[3]  Hui Zhao,et al.  RGD-based strategies for improving antitumor activity of paclitaxel-loaded liposomes in nude mice xenografted with human ovarian cancer , 2009, Journal of drug targeting.

[4]  Sanjiv S Gambhir,et al.  Dual-targeted contrast agent for US assessment of tumor angiogenesis in vivo. , 2008, Radiology.

[5]  Martina A. McAteer,et al.  Magnetic Resonance Imaging of Endothelial Adhesion Molecules in Mouse Atherosclerosis Using Dual-Targeted Microparticles of Iron Oxide , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[6]  D. Boturyn,et al.  Tumor targeting with RGD peptide ligands-design of new molecular conjugates for imaging and therapy of cancers. , 2007, Anti-cancer agents in medicinal chemistry.

[7]  M. Reed,et al.  Neuropilins in physiological and pathological angiogenesis , 2007, The Journal of pathology.

[8]  Dae-Duk Kim,et al.  Enhanced solubility and stability of PEGylated liposomal paclitaxel: in vitro and in vivo evaluation. , 2007, International journal of pharmaceutics.

[9]  R. Bellamkonda,et al.  A dual-ligand approach for enhancing targeting selectivity of therapeutic nanocarriers. , 2006, Journal of controlled release : official journal of the Controlled Release Society.

[10]  R. Govindan,et al.  Novel formulations of taxanes: a review. Old wine in a new bottle? , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  Klaas Nicolay,et al.  MR molecular imaging and fluorescence microscopy for identification of activated tumor endothelium using a bimodal lipidic nanoparticle , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  Qiang Zhang,et al.  Enhanced intracellular delivery and improved antitumor efficacy of doxorubicin by sterically stabilized liposomes modified with a synthetic RGD mimetic. , 2005, Journal of controlled release : official journal of the Controlled Release Society.

[13]  T. Allen,et al.  Liposomes targeted via two different antibodies: assay, B-cell binding and cytotoxicity. , 2005, Biochimica et biophysica acta.

[14]  Robert J. Lee,et al.  A Folate Receptor–Targeted Lipid Nanoparticle Formulation for a Lipophilic Paclitaxel Prodrug , 2004, Pharmaceutical Research.

[15]  R. Kontermann,et al.  Novel RGD lipopeptides for the targeting of liposomes to integrin-expressing endothelial and melanoma cells. , 2004, Protein engineering, design & selection : PEDS.

[16]  T. Allen,et al.  Targeting Stealth liposomes in a murine model of human small cell lung cancer. , 2001, Biochimica et biophysica acta.

[17]  F. Greco,et al.  Paclitaxel-based combination chemotherapy in advanced non-small cell lung cancer. , 2001, Lung cancer.

[18]  J Verweij,et al.  Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation. , 2001, European journal of cancer.

[19]  C. Demangel,et al.  Identification of a peptide blocking vascular endothelial growth factor (VEGF)‐mediated angiogenesis , 2000, The EMBO journal.

[20]  F. Dosio,et al.  Preparation, characterization, cytotoxicity and pharmacokinetics of liposomes containing water-soluble prodrugs of paclitaxel. , 2000, Journal of controlled release : official journal of the Controlled Release Society.

[21]  Oku,et al.  Delivery of contrast agents for positron emission tomography imaging by liposomes. , 1999, Advanced drug delivery reviews.

[22]  Bally,et al.  Clearance properties of liposomes involving conjugated proteins for targeting. , 1998, Advanced drug delivery reviews.

[23]  H. Augustin,et al.  Antiangiogenic tumour therapy: will it work? , 1998, Trends in pharmacological sciences.

[24]  Thomas Boehm,et al.  Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance , 1997, Nature.

[25]  R. Straubinger,et al.  Paclitaxel-liposomes for intracavitary therapy of intraperitoneal P388 leukemia. , 1996, Cancer letters.

[26]  B. Leyland-Jones,et al.  Hypersensitivity reactions from taxol. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  A. Beer,et al.  Application of RGD-containing peptides as imaging probes for alphavbeta3 expression. , 2009, Frontiers in bioscience.